tbuckley/cabot-search huggingface dataset:
A phase II trial of nivolumab for patients with platinum-refractory recurrent or metastatic salivary gland cancer.
Authors: Yoshiaki Nagatani, Naomi Kiyota, Tomoko Yamazaki, Yukinori Asada, Masaaki Higashino, Masahiro Goto, Hironaga Satake, Ichiro Ota, Hirokazu Uemura, Katsunari Yane, Kaoru Tanaka, Takuma Onoe, Shigemichi Iwae, Shigeru Hirano, Yoshinori Imamura, Shiro Kimbara, Taku Nose, Taiji Koyama, Yohei Funakoshi, Hironobu Minami
Journal: Journal of Clinical Oncology (2023)

6092 Background: Salivary gland cancer is rare and has various pathological subtypes. With this rarity and heterogeneity, the therapeutic contribution of chemotherapy, including immune checkpoint inhibitors, for recurrent or metastatic salivary gland cancer (RM-SGC) has not been elucidated. The purpose of this trial was to investigate the efficacy and safety of nivolumab for patients with platinum-refractory RM-SGC. Methods: This open-label, single-arm, multicenter phase II trial was conducted at 9 centers in Japan. Eligible patients had platinum-refractory recurrent or metastatic salivary gland cancer with measurable lesions by RECIST v1.1 and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2. Nivolumab 240 mg/body was administered intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). We set the null hypothesis at 3% and the expected at 15% with a one-sided alfa of 0.1 and power of 80%. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Twenty-four patients (16 males; median age, 65.5 years [range, 34-78 years]) were enrolled between March 2018 and January 2022. Pathological types were salivary duct carcinoma (n = 10), adenoid cystic carcinoma (n = 6), adenocarcinoma not otherwise specified (n = 5), mucoepidermoid carcinoma (n = 2), and acinic cell carcinoma (n = 1). In the majority of cases the primary site was a major salivary gland (n = 21), namely the parotid gland in 16 patients and submandibular gland in 5. The primary endpoint of ORR was 8.3% (2/24, 80% CI, 2.2-20.6%), with 2 partial responses (PR) in patients with salivary duct carcinoma (2/10, ORR: 20.0%). DCR was 29.2% (7/24, 2 in PR and 5 in stable disease), and all of the other 17 patients（70.8%）showed progressive disease (PD) on first disease evaluation at 12 weeks. With a median follow up for survivors of 32.0 months, median PFS and OS were 3.0 months (95% CI, 2.8-3.2 months) and 25.0 months (95% CI, 10.9-39.1 months), respectively. There was no new safety concern with nivolumab monotherapy. Conclusions: This phase II trial of nivolumab monotherapy for patients with platinum-refractory RM-SGC did not meet its primary endpoint of ORR. Although nivolumab monotherapy may be worth further development in salivary duct carcinoma, these results may raise concerns over nivolumab monotherapy for RM-SGC. Translational research to elucidate the immune microenvironment of each pathological type is under investigation. Clinical trial information: UMIN000029636 .
Improving long-term care and outcomes of congenital heart disease: fulfilling the promise of a healthy life
Authors: Zhanhao Su, Yunting Zhang, Xiaoman Cai, Qiangqiang Li, Hong Gu, Yibin Luan, Yihua He, Shoujun Li, Jimei Chen, Hao Zhang
Journal: The Lancet Child & Adolescent Health (2023)
Acting on sex and gender in medical innovation is good for business
Authors: Lavanya Vijayasingham, Evelyne Bischof, Bernadette Ateghang-Awankem, Maryam Rumaney, Mariam Otmani del Barrio, Phaik Yeong Cheah, Ajoke Sobanjo ter-Meulen, Cara Tannenbaum, Rosemary Morgan, Jeannette Wolfe
Journal: BMJ (2023)

Gender equality and PandeMic resPonseActing on sex and gender in medical innovation is good for business Lavanya Vijayasingham and colleagues argue that as well as improving safety and efficacy, considering sex and gender related factors in
Epigenome-wide association studies of allergic disease and the environment
Authors: Andres Cardenas, Raj P. Fadadu, Gerard H. Koppelman
Journal: Journal of Allergy and Clinical Immunology (2023)

The epigenome is at the intersection of the environment, genotype, and cellular response. DNA methylation of cytosine nucleotides, the most studied epigenetic modification, has been systematically evaluated in human studies by using untargeted epigenome-wide association studies (EWASs) and shown to be both sensitive to environmental exposures and associated with allergic diseases. In this narrative review, we summarize findings from key EWASs previously conducted on this topic; interpret results from recent studies; and discuss the strengths, challenges, and opportunities regarding epigenetics research on the environment-allergy relationship. The majority of these EWASs have systematically investigated select environmental exposures during the prenatal and early childhood periods and allergy-associated epigenetic changes in leukocyte-isolated DNA and more recently in nasal cells. Overall, many studies have found consistent DNA methylation associations across cohorts for certain exposures, such as smoking (eg, aryl hydrocarbon receptor repressor gene [AHRR] gene), and allergic diseases (eg, EPX gene). We recommend the integration of both environmental exposures and allergy or asthma within long-term prospective designs to strengthen causality as well as biomarker development. Future studies should collect paired target tissues to examine compartment-specific epigenetic responses, incorporate genetic influences in DNA methylation (methylation quantitative trait locus), replicate findings across diverse populations, and carefully interpret epigenetic signatures from bulk, target tissue or isolated cells.
Comorbidities in palmoplantar pustulosis: a Swedish population-based register study
Authors: Sofia Löfvendahl, Jenny M Norlin, Marcus Schmitt-Egenolf
Journal: British Journal of Dermatology (2023)

This study investigated the comorbidity burden of Swedish patients with palmoplantar pustulosis (PPP) vs. the general population and patients with psoriasis vulgaris (PV). We found a significantly higher comorbidity burden in patients with PPP compared with the general population, represented by higher odds for disease across different categories (metabolic, cerebrovascular, cardiovascular, psychiatric). Although patients with PPP and PV showed similar comorbidity burdens overall, the comorbidity profiles differed significantly. Comorbidities such as type 2 diabetes and chronic obstructive pulmonary disorder, which showed both high prevalence (&amp;gt; 5%) in PPP and higher odds than PV, may be of particular importance for the specific comorbidity burden of PPP.
Risk of myocarditis and pericarditis after a COVID-19 mRNA vaccine booster and after COVID-19 in those with and without prior SARS-CoV-2 infection: A self-controlled case series analysis in England
Authors: Julia Stowe, Elizabeth Miller, Nick Andrews, Heather J. Whitaker
Journal: PLoS Medicine (2023)

An increased risk of myocarditis or pericarditis after priming with mRNA Coronavirus Disease 2019 (COVID-19) vaccines has been shown but information on the risk post-booster is limited. With the now high prevalence of prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we assessed the effect of prior infection on the vaccine risk and the risk from COVID-19 reinfection.
Correction: Can we stop routine biopsy of post-endoscopic mucosal resection scars?
Authors: Nicholas G. Burgess, Michael J. Bourke
Journal: Endoscopy (2023)

Correction to: Can we stop routine biopsy of post-endoscopic mucosal resection scars?Endoscopy 2023; 55(07): 608-610DOI: 10.1055/a-2085-5660
Effects of epileptiform activity on discharge outcome in critically ill patients in the USA: a retrospective cross-sectional study
Authors: Harsh Parikh, Kentaro Hoffman, Haoqi Sun, Sahar F Zafar, Wendong Ge, Jin Jing, Lin Liu, Jimeng Sun, Aaron Struck, Alexander Volfovsky, Cynthia Rudin, M Brandon Westover
Journal: The Lancet Digital Health (2023)

BackgroundEpileptiform activity is associated with worse patient outcomes, including increased risk of disability and death. However, the effect of epileptiform activity on neurological outcome is confounded by the feedback between treatment with antiseizure medications and epileptiform activity burden. We aimed to quantify the heterogeneous effects of epileptiform activity with an interpretability-centred approach.MethodsWe did a retrospective, cross-sectional study of patients in the intensive care unit who were admitted to Massachusetts General Hospital (Boston, MA, USA). Participants were aged 18 years or older and had electrographic epileptiform activity identified by a clinical neurophysiologist or epileptologist. The outcome was the dichotomised modified Rankin Scale (mRS) at discharge and the exposure was epileptiform activity burden defined as mean or maximum proportion of time spent with epileptiform activity in 6 h windows in the first 24 h of electroencephalography. We estimated the change in discharge mRS if everyone in the dataset had experienced a specific epileptiform activity burden and were untreated. We combined pharmacological modelling with an interpretable matching method to account for confounding and epileptiform activity–antiseizure medication feedback. The quality of the matched groups was validated by the neurologists.FindingsBetween Dec 1, 2011, and Oct 14, 2017, 1514 patients were admitted to Massachusetts General Hospital intensive care unit, 995 (66%) of whom were included in the analysis. Compared with patients with a maximum epileptiform activity of 0 to less than 25%, patients with a maximum epileptiform activity burden of 75% or more when untreated had a mean 22·27% (SD 0·92) increased chance of a poor outcome (severe disability or death). Moderate but long-lasting epileptiform activity (mean epileptiform activity burden 2% to <10%) increased the risk of a poor outcome by mean 13·52% (SD 1·93). The effect sizes were heterogeneous depending on preadmission profile—eg, patients with hypoxic-ischaemic encephalopathy or acquired brain injury were more adversely affected compared with patients without these conditions.InterpretationOur results suggest that interventions should put a higher priority on patients with an average epileptiform activity burden 10% or greater, and treatment should be more conservative when maximum epileptiform activity burden is low. Treatment should also be tailored to individual preadmission profiles because the potential for epileptiform activity to cause harm depends on age, medical history, and reason for admission.FundingNational Institutes of Health and National Science Foundation.
Elevated cfDNA after exercise is derived primarily from mature polymorphonuclear neutrophils, with a minor contribution of cardiomyocytes
Authors: Ori Fridlich, Ayelet Peretz, Ilana Fox-Fisher, Sheina Pyanzin, Ziv Dadon, Eilon Shcolnik, Ronen Sadeh, Gavriel Fialkoff, Israa Sharkia, Joshua Moss, Ludovica Arpinati, Shachar Nice, Christopher D. Nogiec, Samuel Terkper Ahuno, Rui Li, Eddie Taborda, Sonia Dunkelbarger, Zvi G. Fridlender, Paz Polak, Tommy Kaplan, Nir Friedman, Benjamin Glaser, Ruth Shemer, Naama Constantini, Yuval Dor
Journal: Cell Reports Medicine (2023)

Strenuous physical exercise causes a massive elevation in the concentration of circulating cell-free DNA (cfDNA), which correlates with effort intensity and duration. The cellular sources and physiological drivers of this phenomenon are unknown. Using methylation patterns of cfDNA and associated histones, we show that cfDNA in exercise originates mostly in extramedullary polymorphonuclear neutrophils. Strikingly, cardiomyocyte cfDNA concentration increases after a marathon, consistent with elevated troponin levels and indicating low-level, delayed cardiac cell death. Physical impact, low oxygen levels, and elevated core body temperature contribute to neutrophil cfDNA release, while muscle contraction, increased heart rate, β-adrenergic signaling, or steroid treatment fail to cause elevation of cfDNA. Physical training reduces neutrophil cfDNA release after a standard exercise, revealing an inverse relationship between exercise-induced cfDNA release and training level. We speculate that the release of cfDNA from neutrophils in exercise relates to the activation of neutrophils in the context of exercise-induced muscle damage.
A Mitochondria‐Targeted NIR‐II AIEgen Induced Pyroptosis for Enhanced Tumor Immunotherapy
Authors: Kaiwu Yu, Binglin Ye, Huang Yang, Xinxin Xu, Zhengwei Mao, Qinghua Zhang, Mei Tian, Haoke Zhang, Hong Zhang, Qinggang He
Journal: Advanced Healthcare Materials (2023)

Abstract Cancer immunotherapy is a favorable strategy for facilitating anti‐tumor immunity, but it shows limited benefits in clinical practice owing to the immunosuppressive tumor microenvironment. Pyroptosis shows great immunostimulatory effect on tumor, whereas the lack of pyroptotic inducer with imaging property has restricted its progress in tumor theranostics. Herein, a mitochondria‐targeted aggregation‐induced emission (AIE) luminogen (TPA‐2TIN) with NIR‐II emission is designed for highly efficient induction of tumor cell pyroptosis. The fabricated TPA‐2TIN nanoparticles can be efficiently taken up by tumor cells and selectively accumulated in tumor for a long term observed by NIR‐II fluorescence imaging. More importantly, the TPA‐2TIN nanoparticles can effectively stimulate immune responses both in vitro and in vivo mediated by the mitochondrial dysfunctions and the subsequent activation of the pyroptotic pathway. Ultimately, the reversal of the immunosuppressive tumor microenvironment significantly enhances the immune checkpoint therapy. This study paves a new avenue for adjuvant immunotherapy of cancer.
Prognostic factors of overall survival (OS) in non-small cell lung cancer (NSCLC) patients after failure on immune checkpoint inhibitors (IO) treated with anticancer vaccine OSE2101 or chemotherapy (CT) in phase 3 ATALANTE-1 randomized trial.
Authors: Benjamin Besse, Enriqueta Felip, Rosario Garcia Campelo, Manuel Cobo, Celine Mascaux, Anne Madroszyk, Federico Cappuzzo, Werner Hilgers, Giampiero Romano, Fabrice Denis, Santiago Viteri Ramirez, Didier Debieuvre, Mohammad Razaq, Wolfgang Schuette, Alona Zer, Pierre Attali, François Montestruc, Berangere Vasseur, Rafal Dziadziuszko, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2023)

e21037 Background: OSE2101 (Tedopi) is an anticancer vaccine that has shown an improvement in overall survival (OS) compared with Chemotherapy (CT) (HR 0.59; p = 0.017) in HLA-A2+ NSCLC patients with IO secondary resistance (ESMO 2021 #47LBA). The objective of this analysis was to identify the prognostic factors of OS in each treatment group. Methods: 118 NSCLC EGFR and ALK negative patients who progressed after sequential CT-IO and who received at least 12 weeks IO (defining IO secondary resistance), were randomized (2:1) in OSE2101 or SoC (docetaxel or pemetrexed). Stepwise multivariate analysis of OS was performed after the selection of factors with p &gt; 0.10. Classical baseline factors (disease stage, histology, patient general status) and treatment effect, including best response (Complete Response CR, Partial Response PR, Stable Disease SD versus Progressive Disease PD), severe adverse events and ECOG PS deterioration, were studied and correlated to OS. Results: The statistically significant prognostic factors of OS in multivariate analysis are described in table below. When PS ≤1 was maintained, median OS with OSE2101 was 14.0 [11.1; 16.8] months and 6.3 [2.9; 8.2] when PS deteriorated &gt; 1 (HR 0.23 [0.13; 0.41]); with CT, median OS was respectively 7.5 [4.4; 10.3] and 7.2 [2.3; 15.7] months (HR 0.92 [0.44; 1.96]). When best response to study treatment was CR/PR/SD, median OS with OSE2101 was 12.6 [8.8;16.8] months and 8.0 [5.5; 11.1] when best response was DP (HR 0.61 [0.36; 1.04]); with CT, median OS was respectively 9.8 [7.4; 13.8] and 5.0 [1.0; 7.2] months (HR 0.34 [0.14; 0.84]. Conclusions: Prognostic factors of OS differ between cancer vaccine OSE2101 and standard CT. Maintenance of good ECOG PS was the most important for OSE2101, while best response (CR/PR/SD) to treatment correlated with longer OS with CT and was not prognostic for OSE2101. This analysis supports the mechanism of action of the cancer vaccine in improving OS by controlling tumor growth regardless of best response. Clinical trial information: NCT02654587 . [Table: see text]
A feasibility study of <sup>177</sup>Lu-PSMA radioligand therapy alternated with radium-223 in patients with bone-metastatic, oligo-metastatic, hormone-sensitive prostate cancer after curative therapy: The DUET study.
Authors: André Vis, Rosemarijn Ettema, Harry Hendrikse, Suzanne van der Gaag, Daniela Elena Oprea-Lager
Journal: Journal of Clinical Oncology (2023)

TPS5113 Background: Previous randomized clinical trials have shown an improvement in overall survival in patients with metastatic castration resistant prostate cancer (mCRPC), who have already failed other therapies, treated with 177Lu-PSMA radioligand therapy (RLT). Although 177Lu-PSMA RLT has shown exciting treatment responses in men with mCRPC and suggests a low toxicity profile, it has not been widely investigated in patients with metastatic hormone-sensitive prostate cancer (HSPCa). As of today, treatment with systemic drugs is proof of concept in advanced or metastatic HSPCa, as well as in other cancer types, and leads to improved oncological outcome, potentially by eradicating micro-metastatic disease. As a bone-seeking calcium mimetic, Radium-223 (Ra-223) is incorporated into new bone stroma, predominantly within sclerotic metastatic deposits. The high-energy of the alpha-particle radiation generates double-stranded DNA breaks, offering a potent and highly localized cytotoxic effect in the target areas. In a phase 3, randomized, double-blind, placebo-controlled study, Ra-223 has proven to significantly improve overall survival (by a treatment comprising 1 injection per month, at a dose of 50 kBq per kilogram of body weight intravenously), as compared with placebo. The optimal therapy in patients with oligometastatic bone HSPCa after previous curative treatment has not yet been defined. Methods: This is a single center, interventional, one-arm phase I-II study that prospectively investigates if a treatment strategy in which two types of cytotoxic RLT, i.e., an alpha-emitter and a beta-emitter, alternatively offered to patients with oligometastatic HSPCa, is feasible and safe. Eight patients with low volume, PSMA expressing, radiological progressive HSPCa (minimal 2 bone metastases, maximal 5, and at 0 to 3 lymph node metastases) will be recruited. In these patients, loco-regional radiotherapy or surgery is not an option anymore. The PSA doubling time in participating patients should be less than 6 months. Primary endpoint: To assess the feasibility and safety in patients with bone metastatic, oligometastatic HSPCa, treated by Ra-223 RLT alternated with 177 Lu-PSMA RLT Secondary endpoints: Toxicity and (serious) adverse events will be monitored and reported in concordance with the NCI CTCAE v5.0; Assessment of the xerostomia inventory; Prostate-specific antigen (PSA) levels on follow-up at 3, 6 and 12-months; Investigative Treatment: Patients enrolled in the trial will receive three intravenous applications of Radium-223, in a dose of 5.5 kBq/kg body weight at t = 0 weeks, t = 4 weeks and t = 8 weeks (±1), and two intravenous applications of 7.4 GBq 177Lu-PSMA RLT at t = 6 weeks and t = 12 weeks (±1). Clinical trial information: NL81658.029.22.
Solid implantable devices for sustained drug delivery
Authors: Elizabeth Magill, Sara Demartis, Elisabetta Gavini, Andi Dian Permana, Raghu Raj Singh Thakur, Muhammad Faris Adrianto, David Waite, Katie Glover, Camila J. Picco, Anna Korelidou, Usanee Detamornrat, Lalitkumar K. Vora, Linlin Li, Qonita Kurnia Anjani, Ryan F. Donnelly, Juan Domínguez-Robles, Eneko Larrañeta
Journal: Advanced Drug Delivery Reviews (2023)

Implantable drug delivery systems (IDDS) are an attractive alternative to conventional drug administration routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours. Therefore, constant drug administration is required to keep drug levels within the therapeutic window of the drug. Moreover, oral drug delivery presents alternative challenges due to drug degradation within the gastrointestinal tract or first pass metabolism. IDDS can be used to provide sustained drug delivery for prolonged periods of time. The use of this type of systems is especially interesting for the treatment of chronic conditions where patient adherence to conventional treatments can be challenging. These systems are normally used for systemic drug delivery. However, IDDS can be used for localised administration to maximise the amount of drug delivered within the active site while reducing systemic exposure. This review will cover current applications of IDDS focusing on the materials used to prepare this type of systems and the main therapeutic areas of application.
Inhibition of YAP1 activity ameliorates acute lung injury through promotion of M2 macrophage polarization
Authors: Lu Liang, Wenyan Xu, Ao Shen, Xiaomei Fu, Huiyu Cen, Siran Wang, Zhongxiao Lin, Lingmin Zhang, Fangyu Lin, Xin Zhang, Na Zhou, Jishuo Chang, Zhe‐Sheng Chen, Chuwen Li, Xiyong Yu
Journal: MedComm (2023)

The balance of M1/M2 macrophage polarization plays an important role in regulating inflammation during acute lung injury (ALI). Yes-associated protein (YAP1) is a key protein in the Hippo-YAP1 signaling pathway and is involved in macrophage polarization. We aimed to determine the role of YAP1 in pulmonary inflammation following ALI and regulation of M1/M2 polarization. Pulmonary inflammation and injury with upregulation of YAP1 were observed in lipopolysaccharide (LPS)-induced ALI. The YAP1 inhibitor, verteporfin, attenuated pulmonary inflammation and improved lung function in ALI mice. Moreover, verteporfin promoted M2 polarization and inhibited M1 polarization in the lung tissues of ALI mice and LPS-treated bone marrow-derived macrophages (BMMs). Additionally, siRNA knockdown confirmed that silencing